Pharmaceutical compositions having improved storage stability

ABSTRACT

The present invention relates to a pharmaceutical composition that provides long-term stability of a hydrolytically labile antipsychotic agent

RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.61/702,881, filed Sep. 19, 2012 and to U.S. Provisional Application No.61/780,862, filed Mar. 13, 2013. The entire contents of theseapplications are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition thatprovides long-term stability of a hydrolytically labile antipsychoticagent.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 4,734,416 and 5,006,528 disclose aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinoneor 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril, as an atypical antipsychotic agent useful in the treatmentof schizophrenia, bipolar disease, depression and other CNS disorders.Aripiprazole has the following chemical structure:

Aripiprazole is sold under the tradename Ability®. It acts as a dopamineD₂ partial agonist, serotonin 5-HT_(1A) receptor agonist and is anantagonist of the serotonin 5-HT_(2A) receptor. Abilify® is currentlyadministered orally on a once-a-day dosing schedule as Abilify®(aripiprazole) Tablets, Abilify Discmelt® (aripiprazole) OrallyDisintegrating Tablets and Abilify® (aripiprazole) Oral Solution. In oneembodiment, Abilify® Injection for intramuscular use is a rapid-actingsolution product for treating agitation associated with schizophreniaand bipolar disease. Poor and variable patient compliance with aonce-a-day dosing schedule of psychiatric drugs has been reported.

Olanzapine(1,2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine)is a second generation antipsychotic drug marketed as Zyprexa®. It isuseful for the treatment of disorders such as schizophrenia, bipolardisorder, psychotic depression, and Tourette syndrome. This activepharmaceutical ingredient acts as an antagonist on 5-HT₂ serotoninreceptors as well as the D₁/D₂ dopamine receptors, while also exhibitinganticholinergic and antimuscarinic properties. Olanzapine belongs to thebenzodiazepine family, and has the following structure:

This compound is disclosed, for example, in U.S. Pat. Nos. 5,229,382 and6,169,084. An extended release intramuscular injection productcontaining the water-insoluble salt olanzapine pamoate monohydrate isapproved for use in schizophrenia.

Long-term stability is a critical consideration of drug formulation,expiry, shelf-life, and manufacturing. As such, stable pharmaceuticalformulations that do not result in drug degradation of these and otherantipsychotics through, e.g., hydrolysis and/or oxidation, are desired.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical compositions comprising: (a) ahydrolytically labile antipsychotic agent; (b) a non-ionic waterinsoluble and/or immiscible ester co-surfactant; (c) a water miscibleand/or soluble non-ionic surfactant; and (d) an aqueous vehicle; whereinthe pharmaceutical composition comprises a minimal amount of theantipsychotic hydrolysis products after standing for a certain period oftime. In an embodiment, the pharmaceutical composition comprises aminimal amount of the antipsychotic hydrolysis products after standingfor a certain period of time at various temperature and humidityconditions. For example, the pharmaceutical composition can compriseless than 50 parts per million, e.g., less than 30 parts per million,e.g., less than 10 parts per million, after standing for up to, or morethan, 24 months. In an embodiment, the pharmaceutical compositioncomprises less than 50 parts per million, e.g., less than 30 parts permillion, e.g., less than 10 parts per million, of the hydrolyzedantipsychotic agent degradation products after standing for at least 1month, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

In an embodiment, the pharmaceutical composition comprises less than 50parts per million, e.g., less than 30 parts per million, e.g., less than10 parts per million, of the hydrolyzed antipsychotic agent degradationproducts at certain temperature and humidity conditions, such as 25° C.,with a relative humidity of 60%; 40° C., with a relative humidity of75%; or 30° C., with a relative humidity of 75%. In an embodiment, thepharmaceutical composition comprises less than 50 parts per million,e.g., less than 30 parts per million, e.g., less than 10 parts permillion, of the hydrolyzed antipsychotic agent degradation products attemperatures of 25° C.-40° C. In an embodiment, the degradation isminimized at temperatures selected from any of 25° C.-40° C., over atime period selected from any of 1 month-24 months, e.g., at least 1month, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.In other embodiments, the pharmaceutical composition comprises less than50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33,32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15,14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 parts per million ofthe hydrolyzed antipsychotic agent degradation products at temperaturesof 25° C.-40° C.

In an embodiment, the non-ionic water insoluble and/or immiscible esterco-surfactant is a sorbitan ester of a carboxylic acid, wherein thecarboxylic acid comprises 4-20 carbon atoms. A non-limiting example ofthis sorbitan ester is sorbitan laurate. In another embodiment, thewater miscible and/or soluble non-ionic surfactant is a polyoxyethylenederivative of a sorbitan ester of a carboxylic acid, wherein thecarboxylic acid comprises 8-14 carbon atoms. A non-limiting example ofsuch a polyoxyethylene derivative of a sorbitan ester is polysorbate 20.

As described herein, the hydrolytically labile antipsychotic agent canbe any number of antipsychotic compounds that are susceptible tohydrolysis. In certain embodiments, the compounds are in prodrug form.In one embodiment, the antipsychotic agent is selected from the groupconsisting of an aripiprazole prodrug (e.g., a compound of Formula I orII), or olanzapine prodrug (e.g., a compound of Formula III, IV or V).Non-limiting examples of such compounds are provided below, as CompoundA or Compound 1:

In an embodiment of the pharmaceutical composition, the hydrolyzed drugproduct that is formed to a minimal extent can be the aripiprazole drugform:

and/or the N-methylene hydroxy compound having the following formula(referred to herein as “the N-hydroxymethyl compound” or“N-hydroxymethyl aripiprazole”):

In a particular embodiment of the pharmaceutical composition, themajority of the antipsychotic agent is dissolved within the non-ionicwater insoluble and/or immiscible ester co-surfactant. In anotherparticular embodiment of the pharmaceutical composition, theantipsychotic agent is dissolved within the non-ionic water insolubleand/or immiscible ester co-surfactant.

In an embodiment, the pharmaceutical composition is injectable.Furthermore, the compositions can be easily resuspended by the user,e.g., through handshaking, in a short time prior to administration.Accordingly, because the pharmaceutical composition does not requirereconstitution (i.e., addition of injection vehicle to drug powder priorto use), the pharmaceutical composition can be referred to herein as“ready to use.”

The composition comprising components (b) and (c) can have thesecomponents at varying ratios. In a particular embodiment, the ratio ofcomponents (b) to (c) is approximately 5 to 2, by weight.

The composition can comprise about 0.2-1 weight percent, about 0.4-0.7weight percent, or about 0.5 weight percent component (b). Whencomponent (b) is sorbitan laurate, the composition can comprise about0.2-1 weight percent, about 0.4-0.7 weight percent, or about 0.5 weightpercent sorbitan laurate. In an embodiment, the composition comprisesnot more than 0.5 weight percent sorbitan laurate.

The composition also can comprise about 0.25-0.45 weight percent, about0.3-0.4 weight percent, or about 0.37 weight percent component (b). Whencomponent (b) is sorbitan laurate, the composition also can compriseabout 0.25-0.45 weight percent, about 0.3-0.4 weight percent, or about0.37 weight percent sorbitan laurate. In a particular embodiment, thecomposition comprises about 0.37 weight percent sorbitan laurate.

The composition can comprise about 0.05-0.8 weight percent polysorbate20, about 0.1-0.3 weight percent polysorbate 20, about 0.2 weightpercent, or about 0.15 weight percent component (c). When component (c)is polysorbate 20, the composition can comprise about 0.05-0.8 weightpercent polysorbate 20, about 0.1-0.3 weight percent polysorbate 20,about 0.2 weight percent, or about 0.15 weight percent polysorbate 20.In a particular embodiment, the composition comprises about 0.15 weightpercent polysorbate 20.

The compositions can have varying amounts of antipsychotic agent in thepharmaceutical composition. For example, the composition can becomprised of 15-35 weight percent, e.g., 20-30 weight percent, e.g.,20-26 weight percent antipsychotic agent. In an embodiment, thecomposition can be comprised of 15-35 weight percent, e.g., 20-30 weightpercent, e.g., 20-26 weight percent aripiprazole prodrug (e.g., acompound of Formula I or II), or olanzapine prodrug (e.g., a compound ofFormula III, IV, or V).

In another embodiment, the composition can be comprised of 15-35 weightpercent, e.g., 20-30 weight percent, e.g., 24-30 weight percent, e.g.,about 26.6 weight percent antipsychotic agent. In one embodiment, thecomposition can be comprised of 15-35 weight percent, e.g., 20-30 weightpercent, e.g., 24-30 weight percent, e.g., about 26.6 weight percentaripiprazole prodrug (e.g., a compound of Formula I or II), orolanzapine prodrug (e.g., a compound of Formula III, IV, or V).

In one embodiment, the pharmaceutical composition is formulated for usein delivering a water-insoluble antipsychotic agent into a host. In apreferred embodiment, the host is human. The composition can be intendedfor parenteral (e.g., intramuscular, intradermal, or subcutaneous)administration. In certain embodiments, the composition is formulatedfor delivery through a needle into a host. Accordingly, the compositionmay be formulated for delivery for injection through a syringe equippedwith a needle, where the end-user resuspends the composition prior touse.

In certain embodiments, the pharmaceutical composition comprises abuffer as the aqueous vehicle. The buffer may be selected from aphosphate, citrate, tartrate, or acetate buffer. In a particularembodiment, the buffer is a phosphate buffer.

Also provided herein are methods of making the pharmaceuticalcompositions described above. The methods involve adding the non-ionicwater insoluble and/or immiscible ester co-surfactant to thehydrolytically labile antipsychotic agent to minimize in vitrodegradation of the agent during standing. In an embodiment of themethod, the non-ionic water insoluble and/or immiscible esterco-surfactant minimizes in vitro degradation of the agent duringstanding at various temperature and humidity conditions.

Accordingly, in one aspect, provided herein is a method for minimizingin vitro degradation of a hydrolytically labile antipsychotic agentcomprising adding to a composition comprising the antipsychotic agentand an aqueous vehicle (a) a non-ionic water insoluble and/or immiscibleester co-surfactant and (b) a water miscible and/or soluble non-ionicsurfactant.

In still another aspect, provided herein is a method for the preparationof an aqueous pharmaceutical composition comprising a hydrolyticallylabile antipsychotic agent, wherein the method comprises adding to acomposition comprising the antipsychotic agent and an aqueous vehicle(a) a stabilizing amount of a non-ionic water insoluble and/orimmiscible ester co-surfactant and (b) a water miscible and/or solublenon-ionic surfactant. When component (a) is sorbitan laurate, thestabilizing amount can be about 0.2-1 weight percent, about 0.4-0.7weight percent, or about 0.5 weight percent sorbitan laurate. In anembodiment, the stabilizing amount is not more than 0.5 weight percentsorbitan laurate.

When component (a) is sorbitan laurate, the stabilizing amount also canbe about 0.25-0.45 weight percent, about 0.3-0.4 weight percent, orabout 0.37 weight percent component (b). In a particular embodiment, thestabilizing amount is about 0.37 weight percent sorbitan laurate.

In embodiments of the method, the resulting formulations are ready touse formulations.

In embodiments of the method, the non-ionic water insoluble and/orimmiscible ester co-surfactant is provided in an amount sufficient tominimize in vitro degradation of the antipsychotic agent. In anotherembodiment, when the ester co-surfactant is sorbitan laurate, about0.2-1 weight percent, about 0.4-0.7 weight percent, or about 0.5 weightpercent sorbitan laurate is an amount sufficient to minimize in vitrodegradation of the antipsychotic agent. In other embodiments, the methodincludes adding not more than 0.5 weight percent sorbitan laurate.

In yet another embodiment, when the ester co-surfactant is sorbitanlaurate, 0.25-0.45 weight percent, about 0.3-0.4 weight percent, orabout 0.37 weight percent is sufficient to minimize in vitro degradationof the antipsychotic agent. In a particular embodiment, the methodincludes adding about 0.37 weight percent sorbitan laurate.

In still another embodiment of the methods, the non-ionic waterinsoluble and/or immiscible ester co-surfactant is provided in an amountproviding less than 50 parts per million, e.g., less than 30 parts permillion, e.g., less than 10 parts per million, of the hydrolyzedantipsychotic agent degradation products after the total compositionstands for at least 24 months.

Also provided herein is a method for treating disorders of the centralnervous system, comprising administering an effective amount of any ofthe preceding compositions to an individual in need of such treatment.

In one embodiment, the disorder is anxiety or depression. In anotherembodiment, the disorder is bipolar disorder. In still anotherembodiment, the disorder is autism-related irritability. In yet anotherembodiment, the disorder is a psychotic condition. The psychoticcondition may be schizophrenia or schizophreniform disorder.Alternatively, the psychotic condition may be acute mania.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic showing in vitro (standing) hydrolysis of aparticular aripiprazole prodrug first to an N-hydroxymethyl hydrolysisproduct and then to aripiprazole. As demonstrated in the exemplificationsection, the formation of these hydrolysis products is minimized invitro (i.e., through standing) in the pharmaceutical formulationsdescribed herein.

FIG. 2 is a graph showing the increased solubility of Compound 1 withincreasing concentration of a non-ionic water insoluble and/orimmiscible ester co-surfactant. The experiments demonstrate that thetotal concentration of the prodrug hydrolysis products was less than 5ppm in all vehicles following vigorous shaking of the suspension for 25days.

FIG. 3 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 25° C., with a relative humidity of 60%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 6 ppm after 12 months of standing or 22 ppm after 24 months ofstanding.

FIG. 4 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 40° C., with a relative humidity of 75%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 16 ppm after 6 months of standing.

FIG. 5 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 30° C., with a relative humidity of 75%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 6 ppm after 12 months of standing or 22 ppm after 24 months ofstanding.

FIG. 6 is a table showing that there are low levels of aldehydeformation in the pharmaceutical compositions described herein. Thisstudy was conducted at 40° C., with a relative humidity of 75%.

DETAILED DESCRIPTION OF INVENTION

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising: (a) ahydrolytically labile antipsychotic agent; (b) a non-ionic waterinsoluble and/or immiscible ester co-surfactant; (c) a water miscibleand/or soluble non-ionic surfactant; and (d) an aqueous vehicle; whereinthe pharmaceutical composition comprises a minimal amount of theantipsychotic hydrolysis products after standing for a certain amount oftime. For example, the pharmaceutical composition comprises less than 50parts per million, e.g., less than 30 parts per million, e.g., less than10 parts per million, of the hydrolyzed antipsychotic agent degradationproducts after standing for up to, or more than, 24 months. In anembodiment, the pharmaceutical composition comprises less than 50 partsper million, e.g., less than 30 parts per million, e.g., less than 10parts per million, of the hydrolyzed antipsychotic agent degradationproducts after standing for at least 1 month, 3 months, 6 months, 9months, 12 months, 18 months, or 24 months.

In an embodiment, the pharmaceutical composition comprises less than 50parts per million, e.g., less than 30 parts per million, e.g., less than20 parts per million, e.g., less than 10 parts per million, e.g., lessthan 7 parts per million, of the hydrolyzed antipsychotic agentdegradation products at certain temperature and humidity conditions,such as 25° C., with a relative humidity of 60%; 40° C., with a relativehumidity of 75%; and 30° C., with a relative humidity of 75%. In anembodiment, the pharmaceutical composition comprises less than 50 partsper million, e.g., less than 30 parts per million, e.g., less than 20parts per million, e.g., less than 10 parts per million, e.g., less than7 parts per million, of the hydrolyzed antipsychotic agent degradationproducts at certain temperatures, such as 25° C., 30° C., or 40° C. Inan embodiment, the pharmaceutical composition comprises less than 50parts per million, e.g., less than 30 parts per million, e.g., less than20 parts per million, e.g., less than 10 parts per million, e.g., lessthan 7 parts per million, of the hydrolyzed antipsychotic agentdegradation products at certain temperatures, such as 25° C.-40° C.,over certain time periods, such as at least 1 month, 3 months, 6 months,9 months, 12 months, 18 months, or 24 months. In an embodiment, thepharmaceutical composition comprises less than 50 parts per million,e.g., less than 30 parts per million, e.g., less than 20 parts permillion, e.g., less than 10 parts per million, e.g., less than 7 partsper million, of the hydrolyzed antipsychotic agent degradation productsat certain temperatures, such as 25° C.-40° C., over certain timeperiods, such as 1 month-24 months. In an embodiment, the degradation isminimized at temperatures selected from any of 25° C.-40° C., over atime period selected from any of 1 month-24 months, e.g., at least 1month, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

In an embodiment, the pharmaceutical composition minimizes formation ofthe hydrolyzed product when the composition is stored at what the WorldHealth Organization refers to as defines “Normal Storage Conditions”(see WHO Technical Report Series, No. 908, 2003, Annex 9 Guide to GoodStorage Practices for Pharmaceuticals, Appendix: Storage and LabelingConditions): storage in dry, well-ventilated premises at temperatures of15-25° C. or, depending on climatic conditions, up to 30° C. Thecompositions provided herein are effective in minimizing drugdegradation through, e.g., hydrolysis, in all climactic zones, as wellas “Normal Storage Conditions” in those zones as defined by the WHO:

Climatic Minimum Zone Temperature Humidity Duration Zone I 21° C. ± 2°C. 45% rH ± 5% rH 12 Months Zone II 25° C. ± 2° C. 60% rH ± 5% rH 12Months Zone III 30° C. ± 2° C. 35% rH ± 5% rH 12 Months Zone IV 30° C. ±2° C. 65% rH ± 5% rH 12 Months Zone IVb 30° C. ± 2° C. 75% rH ± 5% rH 12Months Refrigerated  5° C. ± 3° C. No Humidity 12 Months Frozen −15° C.± 5° C.   No Humidity 12 Months

Examples of regions in climatic zone 1 are: USA, Japan, UK, NorthernEurope, Canada, and Russia.

In an embodiment, the non-ionic water insoluble and/or immiscible esterco-surfactant is a sorbitan ester of a carboxylic acid, wherein thecarboxylic acid comprises 4-20 carbon atoms. A preferred sorbitan esteris sorbitan laurate. In another embodiment, the water miscible and/orsoluble non-ionic surfactant is a polyoxyethylene derivative of asorbitan ester of a carboxylic acid, wherein the carboxylic acidcomprises 8-14 carbon atoms. A preferred polyoxyethylene derivative ispolysorbate 20.

The pharmaceutical compositions provided herein are advantageous becausethey offer superior preservation of the active agent. In particular,studies have demonstrated that the hydrolytically labile antipsychoticagent undergoes minimal in vitro hydrolysis after sitting (e.g., sittingduring storage) for various periods of time (see FIGS. 3-5). This slowdegradation was observed even as the solubility of the agent in theinjection vehicle composition increased, which was unexpected (see FIG.2). Without being bound by theory, it is believed that the slowdegradation of the therapeutic agent can be attributed to the highersolubility of the compound in the non-ionic water insoluble and/orimmiscible ester co-surfactant, e.g., sorbitan laurate, as opposed tothe aqueous portion of the vehicle.

In an embodiment, the pharmaceutical composition comprises less than 50parts per million, less than 30 parts per million, or less than 10 partsper million, of the hydrolyzed antipsychotic agent degradation productsafter standing for at least 24 months. In an embodiment, thepharmaceutical composition comprises less than 50 parts per million,e.g., less than 30 parts per million, e.g., less than 10 parts permillion, of the hydrolyzed antipsychotic agent degradation productsafter standing for at least 1 month, 3 months, 6 months, 9 months, 12months, 18 months, or 24 months.

The pharmaceutical composition can further comprise an aqueous vehicle,such as phosphate buffered saline, as well as any of the pharmaceuticalcomponents described herein.

The pharmaceutical compositions also offer minimized excipient levelswhile co-optimizing both re-suspendability and acceptable injectability,and maintain good physiochemical attributes of the antipsychotic agent.The compositions require reduced resuspension times using, for example,hand shaking. In one embodiment, the pharmaceutical compositions can beresuspended for injection within 1-60 seconds of handshaking.Accordingly, the pharmaceutical compositions described herein can alsobe referred to as “ready to use.”

In addition to the re-suspendability and stability advantages describedabove, the pharmaceutical compositions provided herein result in reducedtissue reactions upon injection.

When the pharmaceutical composition is to be used as an injectablecomposition, including but not limited to injection through a needle orneedle-less injection, it can be formulated into a conventionalinjectable vehicle. Suitable vehicles include biocompatible andpharmaceutically acceptable solution and/or emulsions.

Provided below are representative drawings of the sorbitan esters thatcan be used as component (b) in the pharmaceutical compositionsdescribed herein. Sorbitan laurate can also be referred to as “sorbitanmonolaurate”:

Provided below are representative drawings of the polyoxyethylenederivative of a sorbitan ester of a carboxylic acid used as component(c) in the pharmaceutical compositions:

In a particular embodiment, component (c) is polysorbate 20, sold underthe trademark TWEEN °. The polysorbate can be added in an amount thatreduces surface tension of a drug product or aids in suspensionstability of the drug product.

The ratios of (b) and (c) can vary. In one embodiment, the ratio ofcomponents (b) to (c) is approximately 10 to 0.5, e.g., 10 to 1, e.g., 8to 1, e.g., 5:2, by weight. In another embodiment, the ratio ofcomponents (b) to (c) is approximately 5 to 2, by weight. In stillanother embodiment, the composition comprises component (a), sorbitanlaurate, and polysorbate 20, wherein the ratio of sorbitan laurate andpolysorbate 20 is approximately 5 to 2, by weight. In still anotherembodiment, the composition comprises sorbitan laurate, and polysorbate20, wherein the ratio of sorbitan laurate and polysorbate 20 isapproximately 3 to 1, by weight. In another embodiment, the compositioncomprises sorbitan laurate, and polysorbate 20, wherein the ratio ofsorbitan laurate and polysorbate 20 is approximately 2 to 1, by weight.In yet another embodiment, the composition comprises sorbitan laurate,and polysorbate 20, wherein the ratio of sorbitan laurate andpolysorbate 20 is within the range of approximately 3 to 1-2 to 1, byweight. In a particular embodiment, the composition comprises sorbitanlaurate, and polysorbate 20, wherein the ratio of sorbitan laurate andpolysorbate 20 is approximately a ratio of 3 to a range of 1-2, byweight. In another particular embodiment, the composition comprisessorbitan laurate and polysorbate 20, wherein the ratio of sorbitanlaurate and polysorbate 20 is approximately 3 to 1.2, by weight.

As described in the table below, the sorbitan laurate/polysorbate 20ratio can be approximately 0.625, 1, 1.25, 2, 2.5, or 5, representing arange of 0.625-5:

SML/Polysorbate SML % Polysorbate 20% 20 Ratio 1 0.8 1.25 0.5 0.5 1 0.50.2 2.5 1 0.5 2 0.5 0.8 0.625 1 0.2 5 0.5 0.1 5

The weight percent of components (b) and (c) can vary in thepharmaceutical compositions provided herein. In one embodiment, thecomposition comprises about 0.2-1 weight percent component (b), e.g.,sorbitan laurate. In another embodiment, the composition comprises about0.4-0.7 weight percent component (b), e.g., sorbitan laurate. In stillanother embodiment, the composition comprises about 0.5 weight percentcomponent (b), e.g., sorbitan laurate.

In another embodiment, the composition comprises about 0.25-0.45 weightpercent component (b), e.g., sorbitan laurate. In another embodiment,the composition comprises about 0.3-0.4 weight percent component (b),e.g., sorbitan laurate. In still another embodiment, the compositioncomprises about 0.37 weight percent component (b), e.g., sorbitanlaurate.

In another embodiment, the composition comprises about 0.05-0.8 weightpercent component (c), e.g., polysorbate 20. In yet another embodiment,the composition comprises about 0.1-0.3 weight percent component (c),e.g., polysorbate 20. In still another embodiment, the compositioncomprises about 0.2 weight percent polysorbate 20. In yet anotherembodiment, the composition comprises about 0.15 weight percentpolysorbate 20.

The compositions provided herein can also have varying amounts ofhydrolytically labile antipsychotic agent. In an embodiment, theantipsychotic agent is an aripiprazole prodrug or an olanzapine prodrug.In a particular embodiment, the antipsychotic agent is an aripiprazoleprodrug. In one embodiment, the composition comprises approximately15-35 weight percent aripiprazole prodrug (e.g., a compound of Formula Ior II), or olanzapine prodrug (e.g., a compound of Formula III, IV, orV). In another embodiment, the composition comprises approximately 20-30weight percent aripiprazole prodrug (e.g., a compound of Formula I orII), or olanzapine prodrug (e.g., a compound of Formula III, IV, or V).In still another embodiment, the composition comprises approximately20-26 weight percent aripiprazole prodrug (e.g., a compound of Formula Ior II), or olanzapine prodrug (e.g., a compound of Formula III, IV, orV). In another embodiment, the composition comprises approximately 24-26weight percent aripiprazole prodrug (e.g., a compound of Formula I orII), or olanzapine prodrug (e.g., a compound of Formula III, IV, or V).

In one embodiment, the composition comprises approximately 15-35 weightpercent aripiprazole prodrug (e.g., a compound of Formula I or II), orolanzapine prodrug (e.g., a compound of Formula III, IV, or V). Inanother embodiment, the composition comprises approximately 20-30 weightpercent aripiprazole prodrug (e.g., a compound of Formula I or II), orolanzapine prodrug (e.g., a compound of Formula III, IV, or V). In stillanother embodiment, the composition comprises approximately 24-30 weightpercent aripiprazole prodrug (e.g., a compound of Formula I or II), orolanzapine prodrug (e.g., a compound of Formula III, IV, or V). In aparticular embodiment, the composition comprises approximately 26.6weight percent aripiprazole prodrug (e.g., a compound of Formula I orII), or olanzapine prodrug (e.g., a compound of Formula III, IV, or V).

In an embodiment, the pharmaceutical composition comprises:

-   -   (a) 15-35 weight percent aripiprazole prodrug (e.g., a compound        of Formula I or II) or olanzapine prodrug (e.g., a compound of        Formula III, IV, or V);    -   (b) 0.25-0.45 weight percent sorbitan laurate;    -   (c) 0.2-1 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In another embodiment, the pharmaceutical composition comprises:

-   -   (a) 24-30 weight percent aripiprazole prodrug (e.g., a compound        of Formula I or II) or olanzapine prodrug (e.g., a compound of        Formula III, IV, or V);    -   (b) 0.3-0.4 weight percent sorbitan laurate;    -   (c) 0.1-0.3 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In still another embodiment, the pharmaceutical composition comprises:

-   -   (a) about 26.6 weight percent aripiprazole prodrug (e.g., a        compound of Formula I or II) or olanzapine prodrug (e.g., a        compound of Formula III, IV, or V);    -   (b) about 0.37 weight percent sorbitan laurate;    -   (c) about 0.15 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In an embodiment, the pharmaceutical composition comprises:

-   -   (a) 15-35 weight percent compound I:

-   -   (b) 0.25-0.45 weight percent sorbitan laurate;    -   (c) 0.2-1 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In another embodiment, the pharmaceutical composition comprises:

-   -   (a) 24-30 weight percent compound I:

-   -   (b) 0.3-0.4 weight percent sorbitan laurate;    -   (c) 0.1-0.3 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In still another embodiment, the pharmaceutical composition comprises:

-   -   (a) about 26.6 weight percent compound I:

-   -   (b) about 0.37 weight percent sorbitan laurate;    -   (c) about 0.15 weight percent polysorbate 20; and    -   (d) an aqueous vehicle.

In one embodiment, the pharmaceutical has a high storage stability suchthat the decomposition of a hydrolytically labile antipsychotic prodrug(e.g., aripiprazole prodrug, e.g., compound I) to its antipsychotichydrolysis products will be less than 5 ppm when the composition isstored at 25° C. and 60% relative humidity for 6 months. In oneembodiment, the decomposition of aripiprazole prodrug (e.g., compound I)to N-hydroxymethyl hydrolysis products will be less than 5 ppm when thecomposition is stored at 25° C. and 60% relative humidity for 6 months.

In another embodiment, the decomposition of the hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will not exceed 6 ppm when thecomposition is stored at 25° C. and 60% relative humidity for 9 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will not exceed 6 ppmwhen the composition is stored at 25° C. and 60% relative humidity for 9months.

In another embodiment, the decomposition of the hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will not exceed 14 ppm when thecomposition is stored at 25° C. and 60% relative humidity for 18 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will not exceed 14ppm when the composition is stored at 25° C. and 60% relative humidityfor 18 months.

In still another embodiment, the decomposition of the hydrolyticallylabile a antipsychotic prodrug (e.g., aripiprazole prodrug, e.g.,compound I) to its antipsychotic hydrolysis products will not exceed 24ppm when the composition is stored at 25° C. and 60% relative humidityfor 24 months. In one embodiment, the decomposition of aripiprazoleprodrug (e.g., compound I) to N-hydroxymethyl hydrolysis products willnot exceed 24 ppm when the composition is stored at 25° C. and 60%relative humidity for 24 months.

In another embodiment, the pharmaceutical has a high storage stabilitysuch that the decomposition of the hydrolytically labile antipsychoticprodrug (e.g., aripiprazole prodrug, e.g., compound I) to itsantipsychotic hydrolysis products will be less than 5 ppm when thecomposition is stored at 30° C. and 75% relative humidity for 6 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will be less than 5ppm when the composition is stored at 25° C. and 60% relative humidityfor 6 months.

In yet another embodiment, the decomposition of hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will not exceed 6 ppm when thecomposition is stored at 30° C. and 75% relative humidity for 12 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will not exceed 6 ppmwhen the composition is stored at 30° C. and 75% relative humidity for12 months.

In still another embodiment, the decomposition of hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will not exceed 24 ppm when thecomposition is stored at 30° C. and 75% relative humidity for 24 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will not exceed 24ppm when the composition is stored at 30° C. and 75% relative humidityfor 24 months.

In yet another embodiment, the pharmaceutical has a high storagestability such that the decomposition of a hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will be less than 5 ppm when thecomposition is stored at 40° C. and 75% relative humidity for 3 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will be less than 5ppm when the composition is stored at 40° C. and 75% relative humidityfor 3 months.

In another embodiment, the decomposition of the hydrolytically labileantipsychotic prodrug (e.g., aripiprazole prodrug, e.g., compound I) toits antipsychotic hydrolysis products will not exceed 16 ppm when thecomposition is stored at 40° C. and 75% relative humidity for 12 months.In one embodiment, the decomposition of aripiprazole prodrug (e.g.,compound I) to N-hydroxymethyl hydrolysis products will not exceed 16ppm when the composition is stored at 40° C. and 75% relative humidityfor 12 months.

In certain embodiments, the composition is stored in a sealed (e.g.,septum stoppered), colorless, glass vial.

The aqueous vehicle of the pharmaceutical compositions provided hereincan be a buffer. The buffer may be selected from a phosphate, citrate,tartrate or acetate buffer. In a particular embodiment, the buffer is aphosphate buffer.

The pharmaceutical compositions provided herein can further compriseadditional components. For example, the use of additional wetting agentsor surfactants in a pharmaceutical composition may promote one or moreof the following:

-   -   (1) Surface tension reduction, which may aid in wetting, since a        ‘lower surface tension’ liquid will wet surfaces or particles        more readily than a ‘high surface tension’ liquid. Lowering the        surface tension of a liquid may also decrease the incidence of        foaming. The surface tension of a liquid will be lower as more        surfactant is added;    -   (2) Formation of micelles (i.e., spherical or non-spherical        surfactant structures in solution that have the capability to        dissolve non-soluble components); and/or    -   (3) Increase of suspension physical stability.

The pharmaceutical compositions can also contain an aqueous vehicle,which is a vehicle that dilutes and suspends the drug. The vehicle ofinterest herein is one that is pharmaceutically acceptable (safe andnon-toxic for administration to a human) and is useful for thepreparation of a reconstituted formulation. Exemplary vehicles includesterile water, sterile water for injection (WFI), bacteriostatic waterfor injection (BWFI), a pH buffered solution (e.g., phosphate-bufferedsaline), sterile saline solution, Ringer's solution, or dextrosesolution. The buffer can be phosphate, citrate, tartrate, or acetate. Ina particular embodiment, the vehicle is phosphate-buffered saline, whichis a water-based salt solution containing either sodium chloride orpotassium chloride and either sodium phosphate or potassium phosphate.In one embodiment, the phosphate buffer comprises isotonic saline with5-50 mM phosphate buffer at pH 4.0-9.0, e.g., 5.0-8.0, e.g., 5.0-7.5.

The pharmaceutical compositions can further contain an additionalsurfactant that preferentially adsorbs to an interface between twoimmiscible phases, such as the interface between water and an organicpolymer solution, a water/air interface or organic solvent/airinterface. Suitable surfactants include but are not limited to fattyalcohols such as polyethylene glycols (PEGs) and cetyl alcohol.

Optionally, the pharmaceutical compositions can further comprise adispersant, such as, for example, carboxymethyl cellulose (CMC),carboxymethyl cellulose sodium, cross-linked sodium carboxymethylcellulose, calcium carboxymethyl cellulose, and low substitutedhydroxypropyl cellulose magnesium aluminum silicate, or a mixturethereof. In a particular embodiment, the pharmaceutical compositioncomprises carboxymethyl cellulose.

The pharmaceutical compositions may also optionally comprise anantioxidant to inhibit the oxidation of ingredients. Some examples ofantioxidants include, but are not limited to, ascorbic acid, ascorbylpalmitate, butylated hydroxyanisole, a mixture of 2- and3-tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumiso-ascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha-tocopherol, andpropylgallate.

The pharmaceutical compositions can further include a lipid, e.g., aneutral lipid. Neutral lipids include any lipid that remains neutrallycharged at a pH between about 4 and 9. Neutral lipids include, withoutlimitation, cholesterol, other sterols and derivatives thereof,phospholipids, and combinations thereof. The phospholipids include anyone phospholipid or combination of phospholipids capable of formingliposomes.

They include phosphatidylcholines, phosphatidylethanolamines, lecithinand fractions thereof, phosphatidic acid, phosphatidylglycerols,phosphatidylinositols, phosphatidylserines, plasmalogens andsphingomyelins. The phosphatidylcholines include, without limitation,those obtained from egg, soy beans, or other plant sources or those thatare partially or wholly synthetic or of variable lipid chain length andunsaturation, POPC, OPPC, natural or hydrogenated soy bean PC, naturalor hydrogenated egg PC, DMPC, DPPC, DSPC, DOPC, and derivatives thereof.In one embodiment, phosphatidylcholines are POPC, non-hydrogenated soybean PC and non-hydrogenated egg PC. Phosphatidylethanolamines include,without limitation, DOPE, DMPE and DPPE and derivatives thereof.Phosphatidylglycerols include, without limitation, DMPG, DLPG, DPPG, andDSPG. Phosphatidic acids include, without limitation, DSPA, DMPA, DLPA,and DPPA.

The pharmaceutical compositions can also advantageously employ a densityenhancing agent, such as a sugar, e.g., mannitol or sorbitol, and/or atonicity adjusting agent, such as sodium chloride or glycerol.

Other pharmaceutical carriers that could be used in the pharmaceuticalcompositions provided herein also include water, aqueous methylcellulosesolutions, saline, dextrose solutions, fructose solutions, ethanol, oroils of animal, vegetative, or synthetic origin. The pharmaceuticalcarrier may also contain preservatives, and buffers as are known in theart.

The terms “pharmaceutical composition”, “formulation”, “injectablecomposition,” etc. are used synonymously throughout the application.

The pharmaceutical compositions described herein may also be in the formof an emulsion. The term “emulsion” as used in this specificationdenotes a two-phase system in which one phase is finely dispersed in theother phase. An emulsifier can be used in the pharmaceuticalcompositions to form the emulsion. The term emulsifier, as used by thisinvention, denotes an agent that can reduce and/or eliminate the surfaceand the interfacial tension in a two-phase system. Such an agentpossesses both hydrophilic and lipophilic groups in the emulsifieragent.

The pharmaceutical compositions described herein may also be in the formof adispersion. As used herein, the term “dispersion” is to beunderstood as a mixture in which fine particles of one substance (e.g.,a drug) are scattered throughout another substance (e.g., a liquid).Dispersions include suspensions and colloids.

The methods of the invention include administering the compositionsdescribed herein, thereby obtaining an extended release or sustainedrelease profile in the patient. “Extended-release” or“sustained-release” includes dosage forms whose drug-releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional dosageforms such as a solution or an immediate release dosage form. Anextended release profile includes deliveries that achieve atherapeutically effective amount of the antipsychotic agent, e.g.,aripiprazole prodrug (e.g., a compound of Formula I or II), orolanzapine prodrug (e.g., a compound of Formula III, IV or V), ispresent in the plasma of the individual for at least about 7 days,preferably at least about 14 days, or more preferably at least about 21days alternatively for at least 2, 3, 4, 6 or 8 weeks or as much asthree months.

In one embodiment, the pharmaceutical compositions can be administeredas a single or sole (undivided) dose. However, the composition is alsouseful for those individuals that require constant or chronic therapy,such as those that receive repeated doses over several hours, days,weeks, months, or more. In such dosing regimens, the method can comprisea first administration of a first extended release composition and asecond administration of a second extended release composition. Thesecond composition can be the same, substantially the same or differentas the first and can include the same active agent or a different activeagent. For example, the second composition can be administered at about7 days, or more, such as at least about 14 days, or at least about 17days, after the first administration, where the first administrationresults in the release of agent for a period of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14 days, or more.

The injectable, pharmaceutical compositions described herein can beinjected into a patient in any number of ways. The term “injectable” asused herein refers to a composition that is suitable to be delivered toan individual in an injection, such as with an injection device,including one that employs a syringe or a cartridge, which may be housedin a manual injection device or an auto-injection device, for example.Specifically, the injectable composition is suitable for parenteraladministration. As used herein, the term “parenteral administration”refers to administration through injection or infusion. Parenteraladministration includes, but is not limited to, intravenousadministration, intradermal administration, subcutaneous administrationor intramuscular administration. The term “intravenous administration”means administration into a vein. “Intradermal administration” isinjection into the upper layer of skin (i.e., the dermis), just beneaththe epidermis. “Subcutaneous administration” refers to administrationjust below the skin. “Intramuscular administration” is the injectiondirectly into a muscle.

Antipsychotic Agents

As discussed above, the pharmaceutical compositions provided herein areuseful for the administration of hydrolytically labile antipsychoticagents to a subject. In particular, the pharmaceutical compositionsminimize the formation of the hydrolysis product of the hydrolyticallylabile antipsychotic agent contained therein during standing, such thatthe pharmaceutical composition has an improved shelf life. As usedherein the term “antipsychotic” refers all drugs used to treatpsychosis. Common conditions for which antipsychotics are prescribedinclude schizophrenia, mania, and delusional disorder, althoughantipsychotics are also used to counter psychosis associated with a widerange of other diagnoses. Antipsychotics also act as mood stabilizersmaking them suitable for the treatment of bipolar disorder (even when nosymptoms of psychosis are present). The pharmaceutical compositionsprovided herein are particularly useful for formulating awater-insoluble antipsychotic into an injectable composition.

In one embodiment, the antipsychotic drug of the pharmaceuticalcomposition is an aripiprazole prodrug. The aripiprazole prodrug cancomprise, consist essentially of, or consist of an aripiprazole prodrugin a crystalline, non-crystalline or amorphous form, an aripiprazoleprodrug solvate (including ethanolates and hydrates), or otheraripiprazole prodrug polymorphs.

The term “prodrug” is art-recognized and is intended to encompasscompounds which, under physiological conditions, are converted intoactive compounds, e.g., those described herein. A common method formaking a prodrug is to select moieties that are hydrolyzed or otherwisecleaved under physiological conditions to provide the desired compound.In other embodiments, the prodrug is converted by an enzymatic activityof the host animal.

Preferred aripiprazole prodrugs that can be used in the pharmaceuticalcompositions include the prodrugs described in U.S. Publication No.2011/0003828, which is incorporated herein by reference in its entirety.

In a particular embodiment, the aripiprazole prodrug is a compound ofFormula (I) or Formula (II):

-   -   wherein    -   R^(a) is absent, and R^(b) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹,        —CH₂OC(O)N(R¹)₂ or —C(O)R¹;    -   or    -   R^(b) is absent, and R^(a) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹,        —CH₂OC(O)N(R¹)₂ or —C(O)R¹;    -   R^(c) is —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂ or —C(O)R¹;        wherein each R¹ is independently selected from the group        consisting of hydrogen, substituted or unsubstituted aliphatic,        and substituted or unsubstituted aryl; and    -   wherein each R² is selected from the group consisting of        substituted or unsubstituted aryl and substituted or        unsubstituted heteroaryl;    -   wherein Y^(θ) is a pharmaceutically acceptable counterion; and    -   wherein        represents a single or double bond.

Suitable counterions include, e.g., chloride, bromide, iodide, sulfate,phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate,lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate,pamoate, conjugate bases of organic carboxylic acids, and the like.

In one embodiment of formula (I), the aripiprazole prodrug is a compoundof formula (I′):

-   -   wherein R^(a) is CH₂OC(O)R¹ and wherein R¹ is selected from        substituted or unsubstituted aliphatic.

In a particular embodiment of formula (I′), R¹ is —CH₂OC(O)—(CH₂)₄CH₃(Compound A). In another particular embodiment of formula (I′), R¹ is—CH₂OC(O)—(CH₂)₁₀H₃ (Compound 1). Compounds A and 1 are depicted below:

In an embodiment of the pharmaceutical composition, when thehydrolytically labile antipsychotic agent is an aripiprazole prodrug,the hydrolyzed drug product that is formed to only a minimal extent canbe the aripiprazole drug form:

and/or the N-methylene hydroxy compound having the following formula:

In another embodiment, the antipsychotic drug of the pharmaceuticalcomposition is an olanzapine prodrug. The olanzapine prodrug substancecan comprise, consist essentially of, or consist of the olanzapineprodrug in a crystalline, non-crystalline or amorphous form, anolanzapine prodrug solvate (including for example ethanolates andhydrates), or other olanzapine prodrug polymorphs.

The olanzapine drug substance can also include olanzapine prodrugs ofFormula (III), (IV) or (V):

-   -   wherein R^(3a), R^(3b), and R^(ac) are independently        —CH₂OC(O)R¹, —CH₂OC(O)OR¹, —CH₂OC(O)N(R¹)₂, —C(O)R′ or        —C(O)OC(R⁴)(R⁵)—OC(O)(G¹²)_(m)R⁶;    -   wherein R¹ is independently selected from the group consisting        of hydrogen, substituted or unsubstituted aliphatic, and        substituted or unsubstituted aryl;    -   wherein each R⁴ and R⁵ is independently selected from hydrogen,        C₁-C₃ alkyl, aryl or substituted aryl; preferably, hydrogen or        methyl;    -   wherein G¹² is selected from NH, CH₂, —S— or —O—;    -   wherein m is 0 or 1;    -   wherein R⁶ is selected from C₁₃-C₂₆-alkyl, substituted        C₁₃-C₂₆-alkyl, C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl,        C₁₃-C₂₆-alkynyl, substituted C₁₃-C₂₆-alkynyl,        C₁₃-C₂₆-cycloalkyl, and substituted C₁₃-C₂₆-cycloalkyl,        aryl-C₁₃-C₂₆-alkyl, substituted aryl-C₁₃-C₂₆-alkyl, C₁-C₁₀-aryl,        substituted C₁-C₁₀-aryl, heteroaryl-C₁₃-C₂₆-alkyl, substituted        heteroaryl-C₁₃-C₂₆-alkyl; optionally substituted        C₁₃-C₂₆-alkylaryl, optionally substituted C₁₃-C₂₆-alkenylaryl        and optionally substituted C₁₃-C₂₆-alkynylaryl; and wherein        Y^(θ) is a pharmaceutically acceptable counterion.

Suitable counterions include, e.g., chloride, bromide, iodide, sulfate,phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate,lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate,pamoate, conjugate bases of organic carboxylic acids, and the like.

In one embodiment of formula (III), R^(3a) is —C(O)OCH₂OC(O)R⁶ and R⁶ isselected from C₁₃-C₂₆-alkyl. In a particular embodiment of formula(III), R^(3a) is —C(O)OCH₂OC(O)(CH₂)₁₄CH₃ (Compound O-56). In anotherparticular embodiment of formula (III), R^(3a) is—C(O)OCH₂OC(O)(CH₂)₁₆CH₃ (Compound O-111). In still another particularembodiment of formula (III), R^(3a) is —C(O)OCH₂OC(O)(CH₂)₁₈CH₃(Compound O-112). Compounds O-56, O-111 and O-112 are depicted below:

In one embodiment of formula (IV), R^(3b) is —C(O)OCH₂OC(O)R⁶ and R⁶ isselected from C₁₃-C₂₆-alkyl. In a particular embodiment of formula (IV),R^(3b) is —C(O)OCH₂OC(O)(CH₂)₁₄CH₃ (Compound O-7). In another particularembodiment of formula (IV), R^(3b) is —C(O)OCH₂OC(O)(CH₂)₁₆CH₃ (CompoundO-8). In still another particular embodiment of formula (IV), R^(3b) is—C(O)OCH₂OC(O)(CH₂)₁₈CH₃ (Compound O-9). Compounds O-7, O-8 and O-9 aredepicted below:

Accordingly, aripiprazole, or olanzapine, or a compound of Formula I,II, III, IV, or V can be referred to as an “antipsychosis agent” or“hydrolytically labile antipsychotic agent.”

An “aliphatic group” or “aliphatic” is non-aromatic moiety that may besaturated (e.g. single bond) or contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic, contain carbon, hydrogen or,optionally, one or more heteroatoms, and may be substituted orunsubstituted.

An aliphatic group, when used as a linker, preferably contains betweenabout 1 and about 24 atoms, more preferably between about 4 to about 24atoms, more preferably between about 4 to about 12 atoms, more typicallybetween about 4 and about 8 atoms. An aliphatic group, when used as asubstituent, preferably contains between about 1 and about 30 atoms,more preferably between about 4 to about 19 atoms. In addition toaliphatic hydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may include alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl groups described herein.

In certain embodiments, the aliphatic groups of the present inventionare alkyl chains containing from 5 to 11 carbon atoms. In otherembodiments, the aliphatic groups are alkyl chains containing from 15 to19 carbon atoms.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane, and biphenyl. In an embodiment, aryl is unsubstituted orindependently substituted one or more times with halogen, C₁₋₆ alkyl, orO—C₁₋₆ alkyl.

The term “heteroaryl” embraces unsaturated heterocyclyl radicals.Examples of heteroaryl radicals include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, amino alkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The term “compound” is defined herein to include pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, enantiomers,diastereoisomers, racemates and the like of the compounds having aformula as set forth herein.

Methods of Treatment

The pharmaceutical compositions provided herein can be used fortreatment of a variety of disorders in a subject in need thereof. Forexample, the disclosed compositions may be used to treat conditionsselected from: disorders such as cerebral deficit subsequent to cardiacbypass surgery and grafting, stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage, dementia (including AIDS-induced dementia), Alzheimer'sdisease, Huntington's Chorea, amyotrophic lateral sclerosis, oculardamage, retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, cerebraldeficits secondary to prolonged status epilepticus, migraine (includingmigraine headache), urinary incontinence, substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.), psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, social phobia, obsessive compulsive disorder,and post-traumatic stress disorder (PTSD)), attention deficit disorder(ADD), attention deficit hyperactivity disorder (ADHD), mood disorders(including depression, mania, bipolar disorders), circadian rhythmdisorders (including jet lag and shift work), trigeminal neuralgia,hearing loss, tinnitus, macular degeneration of the eye, emesis, brainedema, pain (including acute and chronic pain states, severe pain,intractable pain, neuropathic pain, inflammatory pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In another embodiment, the present invention provides a method oftreating cardiac and cardiovascular disorders such as angina,arrhythmia, and hypertension, in a patient in need thereof. The methodcomprises administering to the subject a therapeutically effectiveamount of a composition of the invention or a pharmaceuticallyacceptable salt thereof.

The invention further relates to the treatment of fever, diabetes,allergy, asthma, infection, inflammation, and ulcers in a patient inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a composition of the invention or a pharmaceuticallyacceptable salt thereof.

The invention further relates to the treatment of sleep modulationcomprising administration of a composition of the invention. Sleepmodulation includes decreasing the time to sleep onset, increasing theaverage sleep bout length, and increasing the maximum sleep bout length.

In a particular embodiment, the pharmaceutical compositions describedherein can be used to treat anxiety, depression, bipolar disorder,autism-related irritability, and psychotic conditions including acutemania, schizophrenia, and schizophreniform disorder in a subject.

The term “treated,” “treating” or “treatment” includes the diminishmentor alleviation of at least one symptom associated with psychosis or arelated CNS disorder. The term “treated,” “treating” or “treatment” asused in reference to a disease or condition shall mean to intervene insuch disease or condition so as to prevent or slow the development of,prevent or slow the progression of, halt the progression of, oreliminate the disease or condition.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with an injection site reaction.

The term “subject” is intended to include animals, which are capable ofsuffering from or afflicted with dementia associated with psychosis or arelated CNS disorder, including, without limitation, psychoticconditions including acute mania, schizophrenia and schizophreniformdisorder, bipolar disorder, anxiety and depression. Examples of subjectsinclude mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats,cats, mice, rabbits, rats, and transgenic non-human animals. In certainembodiments, the subject is a human, e.g., a human suffering from, atrisk of suffering from, or potentially capable of suffering from any ofthe diseases described herein.

The term “about” or “approximately” usually means within 20%, morepreferably within 10%, and most preferably still within 5% of a givenvalue or range. Alternatively, especially in biological systems, theterm “about” means within about a log (i.e., an order of magnitude),preferably within a factor of two of a given value.

In one embodiment, a therapeutically effective amount of the agent isgiven to a subject using the pharmaceutical compositions providedherein. The term “therapeutically effective amount” is further meant todefine an amount resulting in the improvement of any parameters orclinical symptoms. The actual dose may vary with each patient and doesnot necessarily indicate a total elimination of all disease symptoms. Inthe case of antipsychotics, the management of exacerbations andmaintenance of remission of psychiatric symptoms are main goals oftherapy, and selection of the appropriate drug and dosage in aparticular disease balances these goals with the minimization of adverseevents attributable to the drug.

A therapeutically effective amount of the compound used in the treatmentdescribed herein can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective dose, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

Preferred suitable dosages for the compounds used in the treatmentdescribed herein are on the order of about 1 mg to about 600 mg,preferably about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280,300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560,580 to about 600 mgs total of active agent. Dosing schedules may beadjusted to provide the optimal therapeutic response. For example,administration can be one to three times daily for a time course of oneday to several days, weeks, months, and even years, and may even be forthe life of the patient. Practically speaking, a unit dose of any givencomposition used in the treatment described herein can be administeredin a variety of dosing schedules, depending on the judgment of theclinician, needs of the patient, and so forth. The specific dosingschedule will be known by those of ordinary skill in the art or can bedetermined experimentally using routine methods. Exemplary dosingschedules include, without limitation, administration five times a day,four times a day, three times a day, twice daily, once daily, everyother day, three times weekly, twice weekly, once weekly, twice monthly,once monthly, and so forth. Unit dose preparations provided herein cancontain aripiprazole, a compound of Formula I or a compound of FormulaII in the range of about 20 to about 900, e.g., 60 to about 800, mgs(aripiprazole base equivalents). Unit dose preparations provided hereincan contain olanzapine, a compound of Formula III, or a compound ofFormula IV in the range of 40 to about 500 mgs (olanzapine baseequivalents). Unit dose preparations provided herein can contain acompound of Formula V in the range of 160 to about 1000 mgs (lurasidonebase equivalents).

Preferred amounts according to the selected mode of administration areable to be determined by one skilled in the art. Pharmaceuticalcompositions can be manufactured utilizing techniques known in the art.Typically the therapeutically effective amount of the compound will beadmixed with a pharmaceutically acceptable carrier.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples. Theexamples should not be construed as further limiting.

Example I—Stability Study

FIG. 1 shows in vitro hydrolysis of a particular aripiprazole prodrug toN-methyl-hydroxy hydrolysis products. As demonstrated below, theformation of these hydrolysis products is minimized in vitro (i.e.,through standing) in the pharmaceutical formulations described herein.

The solubility of Compound 1 was determined in vehicles containing 10 mMpH 7 phosphate buffer, 0.2% polysorbate 20 (PS), 0.8% saline, andvarious amounts of sorbitan monolaurate (SML). As shown in FIG. 2,Compound 1 showed increasing solubility with increasing SMLconcentration. At a given SML concentration, the trend of Compound 1concentration as a function of pH is consistent with an estimated pKa of˜7. The total concentration of the hydrolysis products of Compound 1,aripiprazole and N-hydroxymethyl aripiprzole, was found to be less than5 ppm in all vehicles following vigorous shaking of the suspension for25 days. The degradation of dissolved Compound 1 was further followed inthe drug vehicle containing 0.50% SML and 0.2% PS. Without being boundby theory, despite the increase in solubility, the observed slowdegradation of Compound 1 at 25° C., 30° C. and 40° C. can be explainedby higher solubility of Compound 1 in the organic droplets of SML asopposed to the aqueous portion of the vehicle.

FIG. 3 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 25° C., with a relative humidity of 60%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 6 ppm after 12 months of standing or 22 ppm after 24 months ofstanding.

FIG. 4 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 30° C., with a relative humidity of 75%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 16 ppm after 6 months of standing.

FIG. 5 is a table showing in vitro (standing) studies of thepharmaceutical compositions described herein. This study was conductedat 40° C., with a relative humidity of 75%. The study demonstrated thatthe total concentration of the prodrug hydrolysis products did notexceed 6 ppm after 12 months of standing or 22 ppm after 24 months ofstanding.

FIG. 6 is a table showing that there are low levels of aldehydeformation in the pharmaceutical compositions described herein. Thisstudy was conducted at 40° C., with a relative humidity of 75%.

Example II—Prodrug Synthesis Procedures

Synthesis of Aripiprazole Prodrugs

Compound A-1: Preparation of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one

A mixture of Aripiprazole (20 g, 45 mmol), triethylamine (1 mL, 7.1mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide(200 mL) was heated to 80° C. for 20 h. The reaction mixture was cooled,diluted with ethyl acetate (400 mL) and washed with water/brine (1:1,3×500 mL). The organic phase was dried over MgSO₄, filtered andevaporated to dryness under vacuum to give hemi-aminal A-1 as a whitesolid (18.6 g, containing 25% Aripiprazole, 65% yield based on A-1).

Compound 1:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylacetate

A solution of Compound A-1 (50.63 g, 0.105 mol) in anhydroustetrahydrofuran (THF, 80 mL) was treated with acetic anhydride (15.3 mL,0.16 mol) and heated for 2.0 hours at 60° C. (oil-bath). To the abovesolution, triethylamine (2.0 mL, 0.014 mol) was added and stirred for 16hours at 60° C. The solvent was removed using a rotator evaporator. Tothe resulting crude mixture, ethyl acetate (150 mL) and heptane (50 mL)was added. The solution was washed with NaHCO₃ (5% aqueous solution, 250mL). After separation of the two layers, pH of the aqueous layer wasadjusted to above 7. The aqueous layer was further extracted using theorganic mixture. The organic layer was separated and washed with 5%NaHCO₃ solution, followed by deionized water, and brine. The solutionwas dried using anhydrous MgSO₄, filtered and evaporated under vacuum.The resulting product was purified using silica gel columnchromatography using ethanol: ethyl acetate (5:95) as the eluent.Fractions containing the desired product were combined and d-tartaricacid (12.5 g dissolved in 60:5 ethanol: water) was added, resulting inthe precipitation of the desired product (48.78 g, 89% yield). ¹H NMR(CDCl3, 300 MHz) δ 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t,2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s,2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H).

Compound 1:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate

Compound 1 was prepared in an analogous fashion to Compound 1. Thedesired product was isolated as a crystalline solid (0.3 g, 21% yield).The molecular weight was confirmed by mass spectrometer analysis. FIG.2-6 shows the PXRD, IR, Raman, TGA spectrum of the desired product. ¹HNMR (CDCl3, 300 MHz) δ 0.87 (t, 3H), 1.24 (m, 16H), 1.62 (m, 2H), 1.83(m, 2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86(dd, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96(dd, 1H), 7.07 (dd, 1H), 7.14 (m, 2H).

Compound A-28:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbenzylcarbamate

To a solution of hemi-aminal A1 (4 g, 8.4 mmol), 4-dimethylaminopyridine(0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) indichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol)and the reaction mixture stirred for 24 hours. The reaction mixture wasthen heated at 35° C. for 20 hours, cooled and washed with water/brine(1:1, 50 mL). The organic phase was dried over MgSO₄, filtered andevaporated under vacuum. The residue was further purified bychromatography on silica eluting with ethylacetate/dichloromethane/methanol (1:1:0.1) to give the desired productas an off white foam (530 mg, 14% yield). ¹H NMR (CDCl₃, 300 MHz) δ1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H),300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H),6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16(m, 1H), 7.23-7.35 (m, 6H); m/z (M⁺H) 611.12 and 613.10.

Compound A:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexanoate

Compound A was prepared in an analogous fashion to Compound A-28. Thedesired product was isolated as a yellow solid (3.69 g, 87% yield). ¹HNMR (CDCl₃, 300 MHz) δ 0.78 (t, 3H), 1.11-1.28 (m, 4H), 1.40-1.78 (m,6H), 2.20-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00(m, 4H), 3.88-4.00 (m, 2H), 5.75-5.83 (m, 2H), 6.55-6.62 (m, 2H),7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H). m/z (M⁺H) 576.4 and 578.4.

Olanzapine Prodrugs

Synthesis of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A]

To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and oncea clear solution formed, the reaction was cooled to 5° C. To this wasadded chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes.The reaction was stirred at room temperature for 30 min and allowed towarm to room temperature. After 15 min at room temperature the reactionmixture was diluted with dichloromethane (100 mL), then washed with aqsatd NaHCO₃ (75 mL) and water (350 mL). The organic phase was dried overMgSO₄ and filtered. The organic phase was then concentrated under vacuumat 45° C. to a volume of ˜150 mL. The mixture was diluted with ethylacetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. Themixture was cooled to room temperature and the resulting solidprecipitate filtered and washed with ethyl acetate. After drying undervacuum at 35° C. for 90 min chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A] (17.1 g, 73%) was obtained as a yellow solid. ¹H-NMR (300 MHz,CDCl₃) δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m), 5.84-5.69 (1H, m),5.47-5.23 (1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H, m).

General Procedure for the Synthesis of Aliphatic Carboxylic AcidSubstituted Compounds Derived from [A]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A] (1 equiv) in dimethylformamide ((13 mL/g of [A])) was added cesiumcarbonate (1 equiv) and the appropriate aliphatic carboxylic acid (2equiv). The reaction mixture was heated at 60° C. for 2-6 h, untilstarting material [A] had been consumed (loss of starting materialdetermined by TLC). The reaction mixture was cooled, diluted withsaturated aqueous NaHCO₃ (50 mL/g of [A]) and diethyl ether (75 mL/g of[A]). After being stirred for 15 min the mixture was filtered throughcelite and the organic phase separated. This was dried over MgSO₄ andevaporated. The residue was purified by column chromatography on silicaeluting with 30% THF in EtOAc and the product containing fractioncombined and evaporated. The residue was co-evaporated from hexanes.

Compound O-56: (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above with the exception of heating at60° C. for 1 day gave (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.62-7.55 (1H,m), 7.45-7.21 (2H, m), 7.17-7.08 (1H, m), 6.26-6.20 (1H, m), 5.66-5.35(2H, m), 3.90-3.79 (2H, m), 3.68-3.54 (2H, m), 2.47-2.45 (4H, m),2.33-2.24 (8H, m), 1.61-1.50 (2H, m), 1.35-1.15 (24H, m), 0.92-0.81 (3H,m)

Compound O-111: (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above gave (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H,m), 7.46-7.37 (1H, m), 7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19(1H, m), 5.67-5.56 (1.5H, m), 5.38-5.34 (1H, m), 3.91-3.78 (2H, m),3.69-3.54 (2H, m), 2.50-2.40 (4H, m), 2.31-2.24 (6H, m), 1.61-1.50 (2H,s), 1.34-1.20 (30H, m), 0.87 (3H, t). [M+1-1]⁺=653.14.

Compound O-112: (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate

Using the procedure as described above gave (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.51 g, 75%) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H,m), 7.46-7.37 (1H, m), 7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19(1H, m), 5.67-5.57 (1.5H, m), 5.37-5.34 (1H, m), 3.90-3.78 (2H, m),3.69-3.53 (2H, m), 2.49-2.40 (4H, m), 2.32-2.24 (6H, m), 1.61-1.50 (2H,s), 1.34-1.20 (34H, m), 0.87 (3H, t). [M+11]⁺=681.19.

General Procedure for the Synthesis of Compounds 7-9

Synthesis of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C]

To a solution of olanzapine (5.0 g, 16 mmol) in tetrahydrofuran (50 mL)at −78° C. was added tetramethylethylenediamine (2.4 mL, 16 mmol),followed by 2M n-BuLi in hexanes (8.0 mL, 16 mmol) over 5 min. Thereaction mixture was stirred for 15 min and then chloromethylchloroformate (2.1 mL, 24 mmol) added and the reaction mixture stirred afurther 30 min. The reaction mixture was then warmed to roomtemperature, stirred for 1 h and quenched with water (50 mL). Thismixture was diluted with brine (50 mL) and extracted with ethyl acetate(50 mL). The organic phase was dried over MgSO₄, evaporated and theresidue further purified by column chromatography on silica eluting with0.2:1:1 methanol/dichloromethane/ethyl acetate to give chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C] (5.6 g, ˜50% pure by ¹H NMR and LCMS). This was used directly in thenext reaction without further purification. ¹H-NMR (300 MHz, CDCl₃) δ7.02-7.30 (4H, m), 6.45 (1H, s), 5.78-5.92 (1.5H, m), 5.52-5.60 (0.5H,m), 3.50-3.70 (4H, m), 2.35-2.55 (7H, m), 2.32 (3H, s). [M+11]⁺=405.0

General Procedure for the synthesis of aliphatic carboxylic acidsubstituted compounds derived from [C]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(C:1 equiv) in dimethylformamide (13 mL/g of [C]) was added Cs₂CO₃ (1equiv) and the appropriate aliphatic carboxylic acid (2 equiv). Thereaction mixture was heated at 65° C. for 2-6 h, until starting material[A] had been consumed (loss of starting material determined by TLC). Thereaction mixture was cooled, diluted with saturated aqueous NaHCO₃ (50mL/g of [C]) and ethyl acetate (75 mL/g of [C]). After being stirred for15 min the mixture was filtered through celite and the organic phaseseparated. This was dried over MgSO₄ and evaporated. The residue wasfurther purified by column chromatography on silica eluting with 1:9methanol/ethyl acetate and after evaporation of the product containingfractions, the residue was co-evaporated with hexane (2×10 mL/g [C]).

Compound O-7: (hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Using the general procedure described above, employing palmitic acid and1.0 g of the intermediate [C], provided (hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-7) (1.60 g, 39% yield) as a pale yellow oil. ¹H-NMR (300MHz, CDCl₃) δ 7.00-7.25 (4H, m), 6.43 (1H, s), 5.62-5.90 (2H, m),3.51-3.66 (4H, m), 2.30-2.56 (10H, m), 1.58-1.68 (2H, m), 1.20-1.34(26H), 0.87 (3H, t). [M+1-1]⁺=625.07.

Compound O-8: (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Using the general procedure described above, employing stearic acid and2.8 g of the intermediate [C], provided (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-8) (1.44 g, 32% yield) as a pale yellow oil. ¹H-NMR (300MHz, CDCl₃) δ 6.99-7.22 (4H, m), 6.43 (1H, s), 5.62-5.88 (2H, m),3.51-3.66 (4H, m), 2.30-2.66 (10H, m), 1.55-1.70 (2H, m), 1.20-1.34(30H), 0.87 (3H, t). [M+H]⁺=653.21.

Compound O-9: (arachidoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate

Compound O-9 can be made using the general procedure described above,and by employing arachidic acid and the intermediate [C], which couldthen provide (arachidoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound O-9).

Example III—Exemplary Aripiprazole Prodrug Formulation

Amount Per Dose Formulation (% w/w) Compound I 26.6  Sorbitanmonolaurate 0.37  Polysorbate 20 0.15  Sodium Chloride 0.59  CMC NASodium Phosphate Dibasic 0.06  Anhydrous Sodium Dihydrogen Phosphate0.05  Monobasic Dihydrate Water for Injection QS to 100 pH range:5.0-7.4

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications, andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

The invention claimed is:
 1. A pharmaceutical composition comprising:(a) Compound 1

(b) a non-ionic water insoluble and/or immiscible ester co-surfactantthat is a sorbitan ester of a carboxylic acid, wherein the carboxylicacid comprises 4-20 carbon atoms; (c) a water miscible and/or solublenon-ionic surfactant; and (d) an aqueous vehicle; wherein thepharmaceutical composition comprises less than 50 parts per million ofthe hydrolysis product of Compound
 1. 2. The pharmaceutical compositionof claim 1, wherein the pharmaceutical composition comprises less than30 parts per million of the hydrolysis product of Compound 1 afterstanding for at least 24 months.
 3. The pharmaceutical composition ofclaim 1, wherein the water miscible and/or soluble non-ionic surfactantis a polyoxyethylene derivative of a sorbitan ester of a carboxylicacid, wherein the carboxylic acid comprises 8-14 carbon atoms.
 4. Thepharmaceutical composition of claim 1, wherein the sorbitan ester issorbitan laurate.
 5. The pharmaceutical composition of claim 3, whereinthe polyoxyethylene derivative of a sorbitan ester is polysorbate
 20. 6.A pharmaceutical composition comprising: (a) 20-30 weight percentcompound I:

(b) about 0.2-1 weight percent sorbitan laurate; (c) about 0.1-0.3weight percent polysorbate 20; and (d) an aqueous vehicle; wherein thepharmaceutical composition comprises less than 50 parts per million ofthe hydrolysis product of Compound
 1. 7. A method of treatingschizophrenia in a subject in need thereof comprising administering tothe subject the composition of claim
 1. 8. A method of treatingschizophrenia in a subject in need thereof comprising administering tothe subject the composition of claim
 6. 9. A method of treating bipolardisorder in a subject in need thereof comprising administering to thesubject the composition of claim
 6. 10. A method of treating anxiety ina subject in need thereof comprising administering to the subject thecomposition of claim
 6. 11. A method of treating depression in a subjectin need thereof comprising administering to the subject the compositionof claim
 6. 12. A method of treating autism-related irritability in asubject in need thereof comprising administering to the subject thecomposition of claim
 6. 13. A method of treating acute mania in asubject in need thereof comprising administering to the subject thecomposition of claim
 6. 14. The pharmaceutical composition of claim 1,wherein the hydrolysis product of Compound 1 is:


15. The pharmaceutical composition of claim 6, wherein the hydrolysisproduct of Compound 1 is: